Substituted alkyl piperidines



iberepresented-by the general formula:

"R3 is selected from the group consisting of hydrogen, hy-

selected from the group consisting of hydrogen, lower alkyl groups and araikyl Representative f 1 80 thetunsaturated compounds VII 18 carried out wrth'agents groups R and R1 are phenyl, benzyl, thienyl, pyridyl,

pounds of the general formula wherein R3 .is an addiandRzisin the 2- and/or 6-position with respect .tothe 2,739,969 Patented Mar. 27, 1956 United States Patent ice The quaternarysalts of the compoundsyof.the'present inventionnareg prepared in the conventional manner by ireaetingttheg -free ,base' with an alkyl halide, aralkyl zhalideaandnanzvalkyl or aralkyl sulfate. For example, .;theremay.- be used methyl iodide,-ethyl chloride,'isopropyl -2broniide, .dimethyl: sulfate, benzyl chloride, ethyl "-ptoluenesulfonate :andother agentsof these types. The acid addition salts include hydrochloride, sulfate, tartrate, nialeate, citrate and'other non-toxic salt-forming 'a'cids *ofthese types.

..In 'genera l,""the compounds'of the=present invention :rnay be prepare'dby several methods. The method of ChoiCefOLLthe substances of the general formula'wherein The present invention relates to a new group ofcom- 15.'fleXib'ility O -q R, 1 and d,'

pounds ,ofsignificant-pharmacological andzphysiological viiillustratedv by the following formulast 2,739,969 SUBSTITUTED ALKYL PIPERIDINES Nathan Sperber and Domenick Papa,..Bloomfield,1N. .L, assignors to Schering Corporation, Bloomfield, N. 1., a t corporation of New Jersey No Drawing. Application June 9, 1952, Serial No. 292,572

Claims. (Cl. 260-293) action. More particularly, the invention describes a series of substituted alkyl piperidines, their acid and isonicotinic, =6=methylnicotinic, 2,6-dirnethylnicotinic, 6- quaternary salts, showing pronounced antispasmodic and isopropylnicotinic, etc., as such or in the form -of their parasympathetic blocking activity. The invention also thydrochlorides are readily reducible to the corresponddescribes intermediates for preparing these compounds, ingpiperidine:carboxylic acids. as ll as processes, This reaction is carried out in a low pressurehydro- The substituted alkyl piperidines of this invention may genator using platinum oxide catalyst or by high pressure hydrogenation using Raney nickel catalyst. tMethylation of the piperidine compound proceeds smoothly by any of the known methods (for example, formic acid and formaldehyde) and subsequent treatment of the N- methyl compound with thionyl chloride gives the corresponding acid chloride. Reaction of the acid chloride by any of the usual Friedel-Crafts procedures with an aromatic compound, for example, benzene, thiophene, R4 chlorobenzene, methoxybenzene, etc., yields the keto wherein .R and R1 are members of thegroup consisting "fm of yp Treatment Of the latteisubstaqee of aryl, aralkyl, aralkenyl, cycloalkyl, cycloalkene,'hetero- Wlth orgapometallw der1vat1\(e of a halogenated thlo' ,cyclic, alkyl and alkene groups, ,R2 is a lower alkyl group, Phelle, PY py j thljalelet e eyeloalkyl or alkylcompouud yields the tertiary carbinols of formula VI. These substances are for the mostpart high-boiling liquids which can be readily recrystallized to white crystalline solid. Dehydration of the tertiary carbin'ols to Alkylpiperidine 'carboxylic acids such as Z-methyl- R I-R1 droxyl, alkoxyl or acyloxy oran additional bond to the piperidine ring, n is an integer from 1-3 and R4 is such as thionyl chloride, phosphorous oxychloride, phosphorous tribromide, sulfuric acid, oxalic acid, hydroisopropyl, butyl and Others f these general types as chloric acid, etc. The choice of reagents and reaction well as the chloride, bromide, dialkylamino,l.lower alkoxy condltions r ps the unsaturated compounds and'lower alkyl substitution products of the cyclic.co1nformula VII 15 detefmlned y h llature of tile Quantltlee pounds R and R1. The methane derivatives of type .VIII are of particular utility f clinical purposes are the obtained by reduction of theunsaturated compounds VII by known ,methods for the hydrogenation of ethylene tional bond to the piperidine ring, the moietyR"C"R1 'compounde Unlike tertifllly n l fhe is-in lh B ifl with respect t the i ridi e igcompounds.are found in both solid and liquld formand are lower-boiling than the'tertiary alcohols.

With the exception of the alkyl and cycloalkyl types,

pyrimidyl, thiazyl, furyl, cyclohexyl, cyclohexenyl propyl,

piperidine nitrogen.

i be obtained from the corresponding carbinols (J. A. C. S.

,,(J. A. C. vS. 72, 2722 (1950)) which are then trans- I to compounds of the type of VI and VII, respectively,

2,739,969 I I p the piperidine compounds VIII can be made by the following alternate method which employs as intermediate the pyridine derivatives IX. The latter compounds can 1H1 CIHI 70, 4001 (1948); J. A. C. S. 71, 887 (1949)) by re- 5 0H placement of the hydroxyl group by halogen (thionyl chloride) followed by reductive dehalogenation using zinc B and acetic acid or any one of several catalytic pro-" \N cedures. The pyridine compound, on oxidation with po- H: SOaQ-CH: V

formed into the tertiary carbinols XI by the same prov v1 cedures used for the conversion of V to VI. 1 High pressure catalytic hydrogenation of XI simultaneously reduces the pyridine ring, dehydrates the resulting piperidine I carbinols (XII) and saturates the newly formed double Using the N'alkylPlperldlnecal'bflyhc acids In 111 the bond of XIII to yield the methane derivative XIV. Alkylaf f the ethyl or methypesters in the onventional tion of the piperidine compound XIV is carried out by" any of the known methods, for example, formic acid Gngnard reaction Wlth, aralkyl,

and formaldehyde, alkyl halides with alkali, etc. Comcyclic, cycloalkyl or alkyl magnesium halide, the compounds of the type of XII and XIII may also be alkylated tassium permanganate, yields the keto compounds X 10 G inthe same manner.

R R B n R R (in, 1 20 m-d-on nt-d-on m-b ra-d-n II XIII XIV The piperidyl carbinols of type VI can also be prefollowing equation for the diphenyl compound from isopared by the reactions iliustrated by the following equanipecotic acid: tions. R

000R: R(BOH 06H! 0H! COOCgH] 0-031 40 zRMg R or R RLi (cmnsot \N N R CQHBMEBI' R l i l R4 Rs N 5 xxvr It is readily seen that this reaction yields the carbinols xxvm of type VI in one step from the ester of III. This 00 method, as indicated, is, of necessity, limited to those i compounds wherein R and R1 are the same. However, in those cases, this procedure has considerable applica- B i Oe sM tion in view of the number of Grignard reagents of R r and R1, which are readily available. In similar fashion, the corresponding 2- and 3-piperidinccarboxylic acid esters yield the 2- and 3-N-alkylpiperidine substituted C'H CH' CH5 H C m CUE carbinols.

C In general, the alkylpyridine or alkylpiperidinecarboxi ylic acids required for the new compounds of the present invention are not generally available. They may be made B i R 3 2: R by the oxidation of alkylpyridines wherein the preferential oxidation of one alkyl group takes place. For example, i on oxidizing 3-ethyl-6-methylpyridine, there is obtained the 6-methylnicotinic acid and by the oxidation of 2,4,6- c, cmso. (EH1 ii t i ethylpyridine, there can be obtained the 2,6-dimethylisonicotinic acid. Alternately, the alkylpyridine or alkylpiperidinecarboxylic acids can be made by cyclization reactions. Cam In the following equations, there are illustrated general methods which may be used for the synthesis of these acids. These syntheses are not limited to the specific subo stances shown, but can be varied to yield the appropriately 0E cg,so, cm substituted acids by the selection of the proper intern-C:H1Ll

XXX

XXIX VI CtH mediates. For instance, in the following equations, in

place of the methyl group in the-final compounds, one

'can' have ethyl, propyl, isopropyl or butyl by using'the corresponding starting material in the initial step:

pounds of the general formula are obtained wherein R and R1 are the same. The reaction is illustrated by the 1 NH; cm=cn-cooc=m EM EQEQQQQ r ,(QEQ QTQEQQQQQ NH2 000cm,

TCO'OGHE I omcoocini HCHO c om-coomm Na mmy CH3 H: Pd H: N Ni Dh d n e y ra on on N Reduction CH y N OH; on, L

(EH3 (1H;

Substituting ethyl aceto acetate for ethyl acrylate in the p nate p-toluenesulfonate is dissolyed in absolute ethanol above equation there is obtained the ethyl 2,6, 6:trimethyland reduced in a Parr apparatus with hydrogen and N. h 1- i t platinum'oxide. The catalystis filtered oil,- thefiltrate (2) CHPC 0 06235 concentrated in vacuoand the residue dissolved in wat er. 7steps The aqueous-filtrate is made basic withpotassium -cara)2 000235 E bonate, the oily layer extracted with ethergthe ether dried, NH: 0 concentrated and the residue, ethyl- 6-1nethyl-N-methyli 00002115 nipecotate, fractionateds B. P. 94 -96 C./9 mm. To a Gri gnard solution prepared from 12g, of magnesium and CH CH 80 g. of br'omobenzene, there is --added 21- g. of ethyl 6- methyl-N-methylnipecotate; The reaction mixture is -.stirred;and refluxed for ten hours,- decomposed with, dilute (3) COQCaHs l H; CHzCOOCzHs 000 3 POO]: v COQQgH gate .QH -C ;=0 I H $6 on \N CH CH 01 on (4) ([31 Pool: OOOCzHs COOQzH 2cH,-( =on-0o002m NIH-2 CH \N CH: C I c CHONa 0-H CN (5) (1 nooocim n 2- ,Piperidl'lw 0N H01 cm- =o H Q= Na I Acetate OH P0013 cooozm 0009 11. QHs- \N 01 19E,

hydrochloric acid andthe hydrochloride filtered. The hydrochloride is suspended inhot water treate'd with-"% sodium hydroxide and the free base extracted with benzene. The benzene extractsare dried, concentrated and the oily residue solidifies upon cooling. The carbinol melts at 112-113 C. i

EXAMPLEJII 6 -methyZ-N -methyl-S-piperidyldiphenylcarbinol yd o hl rid 1 s The invention is further described-bythe following ex- A benzwe so unon of 6 methyl methylplpendy d h b t "t d amples which are presented only as illustrative com- IP enylcar moi 1s ed W! h hylogen'chlonde t'l "tt ofthe ab'olhd hlo'd ,0- pounds and methods and are not intended to limit the 1 preclpl a Ion c r In y me n e 18 a. pleted. Recrystallization from alcohol yields the hymem .except as the clams drochloride as a White crystalline solid.

EXAMPLE I EXAMPLE III 6-methylN-mez'hyl-3phveridyldiphenylcarbinol i A solution of 33 g..of.ethyl6-methy1nicotinate and 50 6'methyl'NNdmethykglzpendyldlphenylcarbmol g. of methyl p-toluenesulfonate is heated on the steam l e bath forfifteen minutes. Dilution of the thick oil with Refluxing a rnixtureof 6 methyl;N:methyl;3piperidyl- .benaene yields the quaternary salt as a white solid, M. P. diphenylcarbinol with an exce ss of rnethyl i 1 19 "1 2 1'' C. The-crude ethyl 6 methyl-N-methylnicotiobtained the quaternarygsalt ofithis exampl r the ei 7 EXAMPLE 1v 6-methyl-N-methyl-3-benzhydrylidenepiperidine A mixture of 16 g. of 6-methyl-N-methyl-B-piperidyldiphenylcarbinol and 200 ml. of 40-60% sulfuric acid is stirred and heated on the steam bath for ten hours.

The solution is poured on ice, made basic with 50% sodium hydroxide and the oily layer is extracted with ether. The ether extracts are dried,-concentrated and the residual oil is fractionated; B. P. 155-160 C./ 1.0 mm.

EXAMPLE V 6-methyl-N-methy1-3-benzhydrylidenepiperidine I hydrochloride From the free base of Example IV and hydrochloric acid, M. P. 246-247 C.

EXAMPLE VI 6-methyl-N,N-dimethyl.-3-benzhydrylidenepiperidinium iodide A solution of 8.5 g. of the free base of Example IV in methanol and an excess of methyl iodide is refluxed for fifteen minutes. Upon dilution withether, a solid 7 crystallizes, which melts at 204-205 C. after a recrystallization from methanol-ether.

EXAMPLE VII 6-me thyl-N-methyl-3-benzhydrylidenepiperidine citrate From the free base of Example IV and an alcoholic solution of citric acid.

EXAMPLE VIII G-methyI-MN-dimethyl-3-benzhydrylidenepiperidinium bromide To a solution of 4.2 g. of the iodide of the previous example in methanol, there is added an equivalent amount of freshly prepared silver bromide. The mixture is refiuxed and stirred for three hours, filtered and the filtrate concentrated. The crude solid is recrystallized from methanol'ether, M. P. 2l9-220 C. This compound can also be prepared by the direct reaction of methyl bromide and the free base.

EXAMPLE IX 6-methyl-N-methyl-3-benzhydrylpiperidine A solution of one mole of 6-methyl-N-methyl-3- beuzhydrylidenepiperidine in absolute alcohol is reduced with Raney nickel catalyst and hydrogen at an initial pressure of 1,500 lbs. and a temperature of 125 C. The catalyst is removed by filtration, the alcoholic solution concentrated in vacuo and the residue is distilled,

13.1. l54158 C./0.5 mm.; M. P. l08109 C.

EXAMPLE X 6-methyl-N-methyl-3-benzhydrylpiperidine hydrochloride From the base of Example IX and hydrochloric acid.

EXAMPLE XI d-mezhyl-MN-dimethyl-S-benzhydrylpiperidinium iodide From the free base of Example IX with methyl iodide.

EXAMPLE XII 6-methyl-N-ethyl-3-piperidyldiphenylcarbinol This compound is prepared by a method analogous to that described in Example I. Ethyl fi-methylnicotinate is quaternized with ethyl p-toluenesulfonate and the crude salt reduced with platinum oxide. Upon reaction of ethyl 6-methyl-N-ethylnipecotate with an ether solution of phenyllithium, there is obtained G-methyl-N-ethyl-S- piperidyldiphenylcarbinol, M. P. 100-101 C.

8 EXAMPLE XIII 6 meihyI-N-thyl-3-bertzhydrylidenepiperidine' Dehydration of the carbinol of Example XII'with sulfuric acid as described in Example IV, B. P. 162-166 C./ 1-2 mm.

. EXAMPLE XIV 6-methyl-N-ethyl-N-methyl-3-benzhydrylidenepiperidinium iodide The free base of Example XIII with methyl iodide yields a semisolid quaternary which slowly crystallizes from ethanol.

EXAMPLE XV 6-methyl-N-ethyl-3-benzhydrylpiperidine Reduction of the base of Example XIII by the method of Example IX, B. P. 156-160 C./1 mm.

EXAMPLE -XVI 6-methyl-N-isopropyl-li-pipridyldiphenylcarb irwl From ethyl fi-methyl-N-isopropylnicotinate p-toluenesulfonate by the procedure of Example I, M. P. 143-144 EXAMPLE XVII a 6-methyl-N-isopropyl-3-benzhydrylidenepiperidine From the carbinol of Example XVI by the procedure of Example IV, B. P. 168-172" C./2 mm.

EXAMPLE XVIII 6-methyl-N-isopropyl-3-benzhydrylidenepiperidine tartrate Equivalent quantities of tartaric acid and the. free base of Example XVII in alcohol are refluxed for one hour. The mixture is cooled, diluted withdry ether and the tartrate then slowly crystallizes, from this mixture.

' EXAMPLE XIX fi-n-propyl-N-methyl-3-piperidyldipheiiylcarbinol Ethyl -n-propylnicotinate (Monatsh., 81, 83 (1950)) is reacted with methyl p-toluenesulfonate and the quaternary salt reduced Withplatinum oxide in ethanol. The resulting 6-n-propyl-N-methylnipecotate is then'reacted with phenyl-magnesium bromide in either according to the procedure of Example I.

EXAMPLE XX 6-n-propyl-N-methyl-3-benzhydrylideripiperidine From the carbinol of the previous example by the procedure of Example IV, B. P. l-175 C./2 mm.

EXAMPLE XXI 6-n-propyl-N-ethyl-3-benzhydrylidenepiperidine From the carbinol of the previous example by the procedure of Example IV, B. P; 169-172 C./l.5 mm,

9 EXAMPLE XXIV -1 1 Prep-Y --'N ve n d ylide wpiperidifl hydrochloride :From thejreearnine of the previous example and hydrogen chloride in anhydrous ether, the hydrochloride of this example is obtained as a white crystalline solid atter recrystallization from ether-alcohol mixture.

EXAMPLE XXV 6-is0butyl-N-methyl-3-piperidyldiphenylcarbinol Ethyl '6-isobutyl-2-hydroxynicotinate (J. A. C. S., 73,

1368 (1951:) ,is converted to the corresponding 2-chloro compound with phosphorous oxychloride and phosphorous pentachloride. Treatment of the latter with palladiumvoncharcoalcatalyst in alcholic hydrogen chloride with hy- .drogen yields.the ethyl 6-isobutylnicotinate. Formation of themethyl quaternary, reduction with platinum oxide ;-and reaction with phenyllithium in accordance with the procedureof Example XXII yields the carbinol of this example.

EXAMPLE XXVI 6-is0butyl-N-methyl-3-henzhydrylidinepiperidine From thecarbinol of the previous example with sul- :furic acid in accordance with Example IV, B. P. 1 73-177 :C./ 1.5 mm.

EXAMPLE XXVII 6. -,isob utyl N.N dimelhyl 3 benzhydrylidin epiperidinium methyl sulfate From the free amine of the previous example in di- -methyl;sulfate in benzene solution.

EXAMPLE XXVIII 6-isobutyl-N-ethy1-3-benzhydrylidinepiperidine Therequisite carbinol is prepared from ethyl 6-isobutyl- N-,ethylnipecotate by the procedures of Examples 1 and XXII. Dehydration of this carbinol with sulfuric acid in accordance with the instructions of Example IV yields the free amine, B. P. l78181 C./l.5 mm.

EXAMPLE XXIX 6-is0butyl-N-ethyl-3-benzhydrylidinepiperidigze citrate From the free amine of the previous example and anhydrous citric acid in absolute alcohol, this salt is obtained as a white crystalline compound.

EXAMPLE XXX 6-is0buzyl-N-is0pr0pyl-3-benzhydrylidinepiperidine The carbinol is prepared by the procedures of Examples I and XXII from ethyl 6-isobutyl-N-isopropylnipecotate.

Dehydration of the carbinol with sulfuric acidas described in Example IV yields the free base as a viscous, yellow oil, B. P. l82l'85 C./2 mm.

EXAMPLE XXXI 6 isobutyl N ethyl N isopropyl 3 benzhydrylidinepiperz'dinium bromide From the free base of the previous exampleandethyl bromide in anhydrous benzene, one obtains the quaternary of this example as a pale yellow crystalline solid.

EXAMPLE XXXII 4-methyl-N-methyl-3-piperidyldiphenylcarbinol Ethyl 4 -methylnicotinate Ann., 347, 215) is converted;

.to the corresponding nipecotate by the procedure of Example I. Treatment of this reduced acid with-phenylmagnesium bromide yields the carbinol of thisexample as a white crystalline solidafterrecrystallizatio irom ethanol.

5 z' ur acid drogen bromide in ether solution.

9 EX-AMPL XZQH 4. mqrby ,-N-me hy -bw h ry di erin ridine =E m-th2tbine o t v e examp th. 5111- .ll aaccqlfdanee with the procedure. of l'q xatnple IV, B. P. 157-161 C./1 mm.

EXAMPLE.

4 -tmethyl.- ;N.-.methyl 3 benzhydrylidirtepigeridine hydrobromia'e A Erom the free amine of the previous example and hy- EXAMPLE XXXV 4 methyl N methyl 3 benzhydrylidinepiperidine lflllfiq from the free amine of Example XXXIII and tartaric cid in,al cohol, t his tartrate is obtained as a whitegcrystalline compound, after recrystallization from ether-alcohol mixture.

EXAMPLE XXXVI 4-ethyl-N-methyl-3-benzhydrylidinepiperidine The requisiteintermediate, 4-ethylnicotinic (Ben, 3 5, 1363 is carried through the series of transformations shown in Examples I and XXII. The carbinol, on treatment with sulfuric acidas described in Example IV, gives ,the unsaturated amine as a yellowish oil, B. P.

163-166 CT/1.5 mm.

EXAM L XVI 4 ethyl.- N methyl 3 'benzhydryl dinepiperidine ,citrate R finin i a coh i q t ene thgfr emitl 9 t previous example and anhydrous citric acid gives 'the citrate of this example as a,whi te to pale yellow crystalline solid.

EXAMPLE XXXVIII 2,4 dimethyl N-methyl-3-bertzhydrylidinepiperidl e Ethyl 2,4 dimethylnicotinate (Ben, 18, 2022) is carried through. the series of transformations shown inExamples 1 and XXII to yield the 2,4-dimethyl-N-methyl- 3-piperidyldiphenylcarbinol. Dehydration of the carbinol with-:,60% tsulfuric acidas described inExample IV yields the unsaturatedamine boiling at :165-168 C./ 1.5 mm.

' ternary directly reduced with platinum oxide in alcoholic solution. =r'I-he so obtained ethyl 2,6-dimethyl-N-methylnipec otate is then converted to the diphenylcarbinol compound by-thepmcedure ofExample I, which on dehydrationwi thsulfuric acid as described in Example-IV yields the unsaturatedamine of this example as a yellow,vis-

cous oil boiling at l52 -l57 l min.

EXA PL XL zfi-dimethyl-MN-dimethyl;3-l e zhydrylidi eie ridi m iodide rfir mthe ft e as of th t viou fixampl an .m iodide, M. P. 229 230'c.

p-toluenesulfonate for methyl p-toluenesultonate, B. P.

155-159 C./1 mm.

EXAMPLE XLHI 2,6-dimethyl-N-ispropyl-3-benzhydryiidinepiperidine succinate From the flee amine of the previous example and succinic acid in anhydrous alcohol solution, the salt of this example is obtained as a white crystalline compound.

EXAMPLE XLIV 5,G-dimethyi-N-methyl-3-benzhydrylidinepiperidine Ethyl 5,6-dimethyl-2-hydroxynicotinate is converted to the 2-chloro compound as outlined in Example XXV. The halogen is then removed with hydrogen using a palladiurnon-charcoal catalyst and the resulting ethyl 5,6-dimethylnicotinate is carried through the series of reactions shown in Example 1 to yield the 5,6-dimethyl-N-methyl- 3-piperidyldiphenylcarbinol. This carbinol on dehydration with 60% sulfuric acid as described in Example IV gives the unsaturated amine, B. P. 164-169 C./ 1.5 mm.

, EXAMPLE XLV 2-metkyl-N-methyl-3-benzhydrylidinepiperidine Ethyl Z-methylnipecotate (U. S. Patent 2,585,210) is methylated and reacted with phenyllithium to yield the corresponding diphenylcarbinol, M. P. l6l-162 C. This carbinol on dehydration with either 60% sulfuric acid or 48% hydrobromic acid yields the amine of this example as a viscous, yellowish oil, B. P. 160-165 C./1 mm.

EXAMPLE XLVI 2-mezhyl-N-methyl-3-benzhydrylidinepiperidine hydrochloride From the amine of the previous example and hydrogen chloride in ether solution followed by recrystallization from alcohol-ether mixture of the hydrochloride.

EXAMPLE XLVII methyl-N -methyl-3-benzhydrylidinepiperidine S-methylnicotinic acid (Ben, m 23, 1111) is esterified, quaternized, reduced and then treated with phenyllithium as described in Example I to yield the substituted 3-pyridyldiphenylcarbinol. Treatment of this carbinol with potassium bisulfate at 150-190 gives the unsaturated amine boiling at 156-161 C./ 1.5 mm.

EXAMPLE XLVIII 4-methyl-5-ethyl-N-methyl-3-benzhydrylidinepiperidine Ethyl-4-methyl-5-ethylnicotinate is prepared from 4- methyl-5-ethyl-2,6-dihydroxynicotinonitrile (Helv. Chim. Acta, 2, 338 (1919)) by treatment with phosphorous oxychloride and phosphorous pentachloride, reduction, dehalogenation of the 2,6-dichloro compound with palladium on barium carbonate catalyst, followed by hydrolysis of the nitrile and esterification of the resulting acid. The ester so obtained is then quaternized, the quaternary reduced and the substituted nipecotate is then treated with phenyllithium to give the 4-methyl5-ethyl-N-methyl-3- piperidyldiphenylcarbinol. The unsaturated amine is obtained from this carbinol by dehydration with 60% sulfuric acid, B. P. 167-170 C./1-2 mm.

EXAMPLE XLIX 4-methyl-5-ethyl-N-methyl-3-benzhydrylidinepiperidine hydrochloride From the free amine of the previousexample and hydrogen chloride in ether solution.

' 12 EXAMPLE L d-mtliyl-S-ethyl-N-methyl-3-benzhydrylpiperidine citrate Reduction of the unsaturated amine of the previous example by the procedure of Example IX yields the benzhydryl derivative, which on treatment with anhydrous citric acid in absolute alcohol gives the citrate as a white crystalline compound. The citrate may be recrystallized from ethanol.

EXAMPLE L1 (1902)) is converted to ethyl 4,6-dimethylnicotinate' by replacement of the hydroxy group with chlorine followed by reductive dehalogenation as described in the previous examples. The reduced ester is then reactedwith phenyllithium to give the diphenylcarbinol compound, which without isolation is dehydrated to the benzylidenesubstance of this example, B. P. 152-154 C./ 1.5 mm.

EXAMPLE LII 1 -phenyl-1-(6-methyl-N-methyl-3-piperidyl) butanol-I The intermediate, 6-methyl-N-methyl-3-benzoylpiperidine is prepared as follows: A solution of 20 g. of ethyl 6-methyl-N-methylnipecotate and ml. of concentrated hydrochloric acid is heated on the steam bath for six hours. The solution is concentrated to dryness and the solid residue of 6-methyl-N-methylnipecotic acid hydrochloride dried in a vacuum dessicator. The dry acid hy drochloride is converted to the acid chloride with thionyl chloride, the excess thionyl chloride removed and the crude acid chloride suspended in dry benzene. With stirring, granular aluminum chloride is added in portions and the resulting mixture is refluxed for 12 hours. The reaction mixture is poured on dilute hydrochloric acid, the acid layer separated, made basic with 50% sodium hydroxide and the resulting oil ether extracted. The ether extracts are dried, concentrated and the residual oil fractionated, B. P. -138 C./1 mm.

To a solution of n-propyllithium prepared from 25 g. of npropylbromide and 2.8 g. of lithium shot in dry ether, there is added 22 g. of 6-methyl-N-methyl-3- benzoylpiperidine. The reaction mixture is refluxed and stirred for 10 hours. The reaction is worked up in the same manner as Example I to obtain the crude carbinol, M. P. 127-128 C.

EXAMPLE LIII 1 -phenyl-1 -(6-methyl-Nmethyl-3 -piperidylidene)- butane The crude carbinol is dehydrated in the usual manner with 60% sulfuric acid and the unsaturated amine obtained as a viscous yellow oil, B. P. 141-144 C./ 2 mm.

EXAMPLE LIV 1 -phenyl-1 6-methyl-N-methyl-N-ethyI-3- piperidylidene) butane bromide Refluxing a mixture of the free base of the previous example with ethyl bromide yields the quaternary salt of this example as a white crystalline solid.

substituting chlorobenzene for benzene in Example 1.11. The crude carbinol without isolation is dehydrated with 60% sulfuric acid to give the unsaturated amine, B, P.

148-151 C./2 mm.

dehydrated with 60% ple IV; the unsaturated amine boiling at 167-171 C./1

13 EXAMPLE LVI l-p-melhoxyphenyl-I-(6-methyl-N-methylf3- piperidylidene) butane The intermediate, l-p-methoxyphenyl-l'-(6-n1ethyl-N- m ethyl-3-piperidyl)butanol1, is prepared by substituting anisole for benzene in Example LII. Dehydration of the carbinol with sulfuric acid as described in Example I yields the olefin, B. P. 149-153 C./1.5 mm.

EXAMPLE LVII 1 6-methyl-N-methyl-3-piperidylphenyl-Z-thienylcarbinol -Substituting Z-thienyllithium for phenyllithium in Example LII, there is obtained the carbinol of .this example as a viscous yellow oil.

EXAMPLE LVIII 2,4,6-trimethyl-N-methyl-S-benzhydrylidenepiperidine Ethyl 2,4,6-trimethylnicotinate (Ann., 215, 1 (1882)) is quaternized, reduced and the resulting. nipecotate ,(B. P. 99-105 C./ mm.) reactedwith phenyllithium. to give the corresponding 3-piperidyldiphenylcarbinol. De-

hydration of the carbinol by the procedure of Example IV gives the unsaturated amine, B. P. l69l73 C./.0.5 mm.

EXAMPLE LIX 3-ethyl-N-methyl-4-benzhydrylidenepiperidine S-ethylisonicotinic acid (Ben, 35, 1352 (1902)) is transformed by the procedures described in the previous examples into the 3-ethylisonipecotic acid. Esterification of the latter, followed by reaction with phenyllithium ,gives the diphenylcarbinol, which without isolation is dehydrated with 60% sulfuric acid as describedin Example IV. The free base is obtained as a viscous .-.yellow oil boiling at 160-164 C./ 1.5 mm.

EXAMPLE LX 3-elhyl-N-methyl-N-isopropyl-4-benzhydrylidenepiperidinium chloride From the free base of the previous example in isopropyl chloride in ether solution the quaternary is obtained as a white crystalline solid which may be recrystallized from a mixture of alcohol-ether.

EXAMPLE LXI 4,6-dimethyl-5-ethyl-N-methyl-3-benzhydrylidenepiperz'dine 4,6-dimethyl-5-ethyl-3-cyano-2-pyridone (I. A..C.- S., 70, 3713) is converted to the 2-chloro-compound, the

latter dehalogenated with palladium barium carbonate catalyst to 4,6-dimethyl-5-ethyl-3-cyan0pyridine, which on hydrolysis, followed by esterification gives'the 4,6- dimethyl-S-ethylnicotinic acid. Treatment with methyl p-toluenesulfonate reduction and reaction withphenyllithium or phenylmagnesium bromide as described in Example I yields the 4,6-dimethyl-4-ethyl-N-methyl-3- piperidyldiphenylcarbinol. The crude carbinolis .then

sulfuric acid as described in'Exam- EXAMPLE LXII 4,6-dimethyl-5-ethyl-N-methyl-N-is0pr0pyl-3 benzhydrylidenepiperidinium bromide From-the free amine of the previous example and isopropyl bromide in ether solution the quaternary is obtained as a white crystalline solid, recrystallizable from alcohol-ether mixture.

EXAMPLE LXHI Phenyl-N-cyclohexenyl-6-methyl-N-methylpiperidylidenemethane 'The intermediate, 6-methyl-N-methyl-3 benzoylpiperi- .:is obtained asa white, crystalline compound melting at petroleum ether.

-of Example XL nate, ethyl p-toluene sulfonate. The amine is a somewhat ethyl-6-methylnicotinate. ,to the compound of, this example proceeds by. the series .dine, prepared. -as'---in Example LII, is reacted .-witl1 A -cyclohexenyl'i chloride "Via; the :lithium derivative. The resulting carbinol is dehydrated at -185 with potassium bisulfate and the doubly unsaturated amine thereby obtained is a yellowish oil, B. P. l.60 162 C./1-2 mm.

EXAMPLE LXiV Plzenylbenzyl-6-methyl-N-methyl-3-piperidylidenemethane The intermediate, 6-rnethyl-N-methyl-3-benzoylpiperidine, described in Example; LII, is treated with one equivalent of benzylmagnesium chloride. The resulting carbinol, without purification, is dehydrated with sulfuric acid as described in Example IV and the unsaturated amineds obtained as a yellowishoil, B. P. 162-165 C./-

l.2 mm

EXAMPLE LXV 6-pr opyl-N-methyl-4-benzhydrylidenepiperidine Ethyl, butyrylpyruvate (J. C.; S., 81 1490). is condensed .with cyanoacetamide and diethylamine in alcohol to yield ethyl 6-propylisonicotinate by the same seriesof transformations used to prepare 6-ethylisonicotinate (J. O. C., 6, 70 A (1941)). 6-propyl-N-methyl-4-benzhydrylidenepiperidine is then prepared from 6-propylisonicotinate according to the procedure described in Examples I and IV,- BrP. 169-1729 C./1.5 mm.

2-.-methyl-N,N-dimethyl-3-benzhyd ylidenepiperidinium iodide -,Fr,om the unsaturated amineof Example XLV and methyl iodide, M. P. 259.260 C.

EXAMPLE LXVIII G-methyl-N-methyl-4-piperidyldiphenylcarbinol Ethyl acetopyruvate and cyanoacetamide are condensed by the procedure described in Example LXV and yields Conversion of this substance of transformations described in Examplel. The carbinol l7 2-173 C. after recrystallization from benzene- EXAMPLE LXIX 6-methyl-N-methyl-4-benzhydrylidenepiperidine Dehydration ofthe carbinol; of the-previous example -.-with sulfuric acidrgives the unsaturated amineof this-ex- .ample, B. P. 151+153 C./0.5,mm.

EXAMPLE LXX 6-methyl-N,N-a'imethyl-4-benzhydrylidenepiperidinium methylsulfate The free amine of the previous example with dimethyl sulfate in benzene solution yields this quaternary salt,

C. after recrystallization from methanolether.

EXAMPLE LXXI 2,6-dimethyl-N-mezhyl-4-benzhydrylidinepiperidine Ethyl-2,6-dimethylisonicotinate is carried through the series of transformations described in Example I to yield the appropriately substituteddipheuyl carbinol. The latter, ondehydration with sulfuric acid as described in the previous examples, gives the unsaturatedhamine ofthis example as a white crystalline solid, M. P. 111-112 C. after recrystallization from petroleum ether.

EXAMPLE LXXII 2,6-dimethyl-N,N-dimethyl-4-benzhydrylidenepiperidinium methyl sulfate The free base of the previous example, on treatment with dimethylsulfate in benzene solution, yields the quaternary salt as a white crystalline solid.

EXAMPLE LXXIII fi-isopropyl-N-methyl-3-benzhydrylidenepiperidine Ethyl-6-isopropyl-Z-hydroxynicotinate (prepared by the procedure described in JACS 73, 1368 (1951) from methylisopropyl ketone) is converted to the corresponding 2-chloro compound with phosphorous oxychloride and phosphorous pentachloride and dehalogenated with palladium-on-carbon. The resulting ethyl-6-isopropylnicotinate is converted to the unsaturated amine of this example by the procedures of Example XXV and XXVI, B. P. 169-173" C.

EXAMPLE LXXIV Z-ethyl-N-methyl-3-benzhydrylidenepiperidine Ethyl-Z-ethylnipecotate is prepared by a method analogous to that described in U. S. Patent 2,585,210. Ethyl- (2-cyanoethyl) propionylacetate is reduced and cyclized to ethyl-2ethylnipecotate, methylated with formaldehyde and palladium-on-carbon to yield ethyl-Z-ethyl-N-methylnipecotate and then by the series of transformations of Example XLV converted to the unsaturated amine of this example, B. P. l63-167 C./ 1 mm.

EXAMPLE LXXV Z-isopropyl-N-methyl-3-benzhydrylidenepiperidine The reduction and cyclization of ethyl-(Z-cyanoethyl) isobutyrylacetate yields ethyl 2 isopropylnipecotate. Methylation gives the N-methyl derivative and the latter by the process of Example XLV is converted to the unsaturated amine of this example, B. P. 172-176" C./1 mm.

EXAMPLE LXXVI 2,6-diethyl-N-methyl-3-benzhydrylidenepiperidine EXAMPLE LXXVII 2,6-diethyl-N-methyl-3-benzhydrylidenepiperidine hydrochloride From the amineof the previous example and hydrogen chloride in ether solution, the hydrochloride, after recrystallization from alcohol-ether is obtained as a white crystalline compound.

EXAMPLE LXXVIII 2,6-diethyl-N-ethyl-3-berizhydrylidenepiperidine By the procedure of Example LXXVI substituting ethylp-toluenesulfonate for methyl-p-toluenesulfonate, B. P. 168-171 C./1 mm.

16 EXAMPLE LXXIX 2,6-diethyl-N,N-diethyl-3-benzhydrylidene piperidinium bromide By reacting the amine of the previous example with ethyl bromide,- this quaternary salt is obtained as a white crystalline compound after recrystallization from alcoholether.

EXAMPLE LXXX 2,6-diz'sopropyl-N-methyl-3-benzhydrylidene piperitline By the procedure of Example LXXVI, substituting ethyl isobutyrylacetate for ethyl propionylacetate, the symmetrical unsaturated amine is obtained as a viscous yellow oil, B. P. 170174 C./l mm.

EXAMPLE LXXXI 6,6-dimethyl-N-methyl-3-benzhydrylidenepiperidine l39-142 C./,3 mm.

One hundred grams of N-methyl-N-Z-carbethoxyethylfi-valine ester is cyclized with sodium and xylene (JACS 68, 1239 (1946)) to yield ethyl-6,6-dimethyl-N-methyl- 4-keto-nipecotate, the latter reduced with platinum oxide and hydrogen inabsolute' ethanol to the corresponding 4-hydroxy compound and after dehydration with potassium bisulfate at 150 the 6,6-dimethyl arecoline is reduced with platinum oxide in ethanol to ethyl-6,6-dimethylnipecotate, B. P. -107 C./ 8 mm. This ester after N-methylation is treated with phenyl lithium in accordance with the'procedure of Example I and yields the crude diphenylcarbinol, which, without purification, is dehydrated with 60% sulfuric acid to the unsaturated amine. This substance is a somewhat viscous, yellowish oil boiling at 167-17 1 C./ 1 mm.

EXAMPLE LXXXII 2,6,6-rrimethyl-N-methyl-3-benzhydrylidenepiperidine The intermediate, N-methyl-N 2 carbethoxypropylfl-valine ester is prepared as follows: A mixture of g. of ethyl acetoacetate and g. of fl-valine ester is heated on the steam bath overnight, alcohol added and the solution reduced with platinum oxide, hydrogen and formaldehyde to give the diester, B. P. 134-138 C./2 mm.

The diester, N-methyl-N-Z-carbethoxypropyl-B-valine ester is cyclized with sodium and xylene and by the same series of transformations described in the previous example gives ethyl-2,6,6-trimethyl-N-methylnipecotate.

This trimethyl ester is converted to the corresponding diphenylcarbinol by the series of reaction described in Example I and after dehydration of the carbinol the unsaturated amine boils at 171-l74 C./1 mm.

Additional compounds which can be prepared by the procedures of the previous examples are the following:

6-n-propyl-N-isopropyl-3-benzhydrylidenepiperidine 6-n-propyl-N-butyl-3-benzhydrylidenepiperidine 6-isopropyl-N-methyl-3-benzhydrylidenepiperidine 6-isopropyl-N-methyl-3-piperidyldiphenylcarbinol 6-isopropyl-N-methyl-3-benzhydrylpiperidine 6-isopropyl-N-ethyl-3-piperidyldiphenylcarbinol fi-isoproply-N-ethyl-Zi-benzhydrylidenepiperidine 6-isopropyl-N-ethyl-3-benzhydrylpiperidine 4-methyl-N-ethyl-3-benzhydrylidenepiperidine 2,4-dimethyl-N-ethyl-3-piperidyldiphenylcarbinol 2,4-dimethyl-N-ethyl-3-benzhydrylidenepiperidine 2,4-dimethyl-N-isopropyl-3-piperidyldiphenylcarbinol 1 7 2,4-dimethyl-N-isopropyl-3-benzhydrylpiperidine 2,6-dimethyl-N-isoproply-3-piperidyldiphenylcarbinol 2,6-dimethyl-N-isoproply-3-benzhydrylidenepiperidine 2,6-dimethyl-N-isopropyl-3-benzhydrylpiperidine 5,6-dimethyl-N-isopropyl-3-benzhydrylidenepiperidine Z-methyl-N-ethyl-3-piperidyldiphenylcarbinol Z-rnethyl-N-ethyl-3-benzhydrylidenepiperidine 2-methyl-N-isopropyl-3-benzhydrylidenepiperidine 4,6-dimethyl-N-ethyl-3-benzhydrylidenepiperidine 1 p chlorophenyl-1-( 6-methyl-N-isopropyl-3-piperidyl) butanol-l l p chlorophenyl-1-(6-methyl-N-isopropyl-3-piperidylidene) butane l-p-methoxyphenyl- 1- 6-methyl-N-ethyl-3-pip eridylidene) butane 6 methyl N methyl-3-piperidylidenephenyl-Z-thiazolylmethane 6 methyl N-methyl-3-piperidylidenephenyl-2-pyrimidylmethane 6-methyl-N-ethyl-4-benzhydrylidenepiperidine 6-methy1-N-isopropyl-4-benzhydrylidenepiperidine 6-ethyl-N-isopropyl-4-benzhydrylidenepiperidine 3-methyl-N-isoproply-4-benzhydryliclenepiperidine 2,4,6-trimethyl-N-isopropyl-3-benzhydrylidenepiperidine Phenyl p-methylpheny1-( 6-methyl-N-methyl-3-piperidyli dene)methane Phenyl p methylphenyl-(2,6-dimethyl-N-methyl-3-piperidylidene)methane wherein R and R1 are members of the group consisting of phenyl, chlorophenyl, methoxyphenyl, benzyl, cyclohexenyl and lower alkyl, R2 is a lower alkyl group; n is an integer from 1 to 3, R4 is selected from the group consisting of hydrogen and lower alkyl groups, and the quaternary and acid addition salts thereof.

2. Piperidylidene compounds of the class consisting of bases of the general formula 18 wherein R and R1 are phenyl and R2 and R4 are lower alkyl groups and the quartenary salts and acid addition salts thereof.

3. Piperidylidene compounds of the class consisting of bases of the general formula wherein R is a phenyl and R1, R2 and R4 are lower alkyl groups and the quaternary salts and acid addition salts thereof.

4. Piperidylidene compounds of the class consisting of bases of the general formula wherein R and R1 are phenyl and R2 and R4 are lower alkyl groups and the quaternary salts and acid addition salts thereof.

5. Piperidylidene compounds of the group consisting of the bases of the general formula wherein R and R1 are phenyl andRz and R4 are lower alkyl groups and the quaternary salts and acid addition salts thereof.

6. 2,6-dimethyl-N-methyl-3-benzhydrylidenepiperidine.

7. 6-methyl-N-methyl-3-benzhydrylidenepiperidino.

8. 1 phenyl 1( 6-methy1-N-methyl-3-piperidy1idene)- butane.

9. Z-methyl-N-methyl-3-benzhydrylidenepiperidine.

10. 2,6-dimethyl-N,N-dimethyl-3-benzhydrilidenepiperidinium iodide.

References Cited in the file of this patent UNITED STATES PATENTS 2,599,364 Berger et a1 June 3, 1952 2,599,365 Berger et al. June 3, 1952 2,604,473 Sperber et al July 22, 1952 

1. PIPERIDYLIDENE COMPOUNDS OF THE GROUP CONSISTING OF BASES OF THE GENERAL FORMULA 